The present application is a continuation of international patent application no. PCT/EP00/09097, filed Sep. 18, 2000, designating the United States of America, the entire disclosure of which is incorporated herein by reference. Priority is claimed based on Federal Republic of Germany patent application nos. 199 48 436.8, and 199 48 434.1, both filed Oct. 8, 1999.
The present invention relates to substituted bicyclic imidazo-5-yl-amines and medicaments comprising these compounds.
Individual representatives from the class of bicyclic imidazo-5-yl-amines are described in EP-A-0 518 033. These compounds carry aromatic substituents bonded via a short alkyl bridge on the imidazole nitrogen which does not belong to the fused ring system. The compounds described in EP-A-0 518 033 as potent angiotensin antagonists which can be employed in medicaments for treatment of circulatory diseases such as high blood pressure.
Attempts have subsequently been made also to prepare those bicyclic imidazo-5-yl-amines which are not substituted on the imidazole nitrogen which does not belong to the fused ring system. However, these attempts had no (K. Groebke et al., Synlett 1998, 661) or only little success (H. Bienayme, K. Bouzid, Angew. Chem. 1998, 110 (16), 2349).
The present invention was therefore based on the object of providing bicyclic imidazo-5-yl-amines which are not substituted on the imidazole nitrogen which does not belong to the fused ring system, and medicaments comprising these compounds.
The invention therefore provides bicyclic imidazo-5-yl-amines of the general formula I 
wherein
R1 denotes C(CH3)3, (CH2)6CN, optionally substituted phenyl, C4-C8-cycloalkyl, CH2CH2R (R=4-morpholino), 1,1,3,3-tetramethylbutyl or CH2Ra, wherein Ra represents hydrogen, C1-C8-alkyl (branched or unbranched), optionally substituted phenyl, CO(ORxe2x80x2) (where Rxe2x80x2=C1-C8-alkyl (branched or unbranched)), PO(ORxe2x80x3)2 (where Rxe2x80x3=C1-C4-alkyl (branched or unbranched)) or Si(RxRyRz) (where Rx, Ry and Rz in each case independently of one another are C1-C8-alkyl (branched or unbranched), C4-C8-cycloalkyl or phenyl),
R2 denotes hydrogen; CORb, wherein Rb represents hydrogen, C1-C8-alkyl (branched or unbranched), C3-C8-cycloalkyl, CH2CH2CO(ORxe2x80x2) (where Rxe2x80x2=C1-C8-alkyl (branched or unbranched)), adamantyl, optionally substituted phenyl, optionally substituted 1-naphthyl, 2-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, thiazolyl or furoyl, CH2Rc, wherein Rc represents hydrogen, C1-C8-alkyl (branched or unbranched) or optionally substituted phenyl; CH2CH2Rd, wherein Rd represents optionally substituted phenyl; or CONHRe, wherein Re represents phenyl,
R3 denotes C1-C8-alkyl (branched or unbranched), C3-C8-cycloalkyl, optionally substituted phenyl, optionally substituted 1-naphthyl, 2-naphthyl, quinoline, anthracene, phenanthrene, benzothiophene, benzofurfuryl, optionally substituted pyrrole, 2-pyridyl, 3-pyridyl, 4-pyridyl, optionally substituted furfuryl or optionally substituted thiophene,
X denotes CR5, N or S, and
Y, in the case where X denotes S, denotes CR6 or N, and in all other cases denotes N,
wherein the broken line in the structural element: 
xe2x80x83means that in the cases where X denotes S, Y is linked via a double bond with the C atom carrying R4, and in all other cases one of the groups X or Y is linked via a double bond with the C atom carrying R4 and the other particular group carries an additional hydrogen,
R4, R5 and R6 independently of one another denote hydrogen, C1-C8-alkyl (branched or unbranched); fluorine; chlorine; bromine; CF3; CN; NO2, NHRf, wherein Rf represents hydrogen, C1-C8-alkyl (branched or unbranched) or optionally substituted phenyl; SRg, wherein Rg represents hydrogen, C1-C8-alkyl (branched or unbranched), phenyl, pyridine, benzyl or fluorenyl; ORh, wherein Rh represents C1-C8-alkyl (branched or unbranched), optionally substituted phenyl or CO(ORxe2x80x2) (Rxe2x80x2=C1-C8-alkyl (branched or unbranched)); CO(ORxe2x80x2) or CH2CO(ORxe2x80x2), wherein Rxe2x80x2 in each case has the abovementioned meaning or in the case of the group CH2CO(ORxe2x80x2) also denotes hydrogen, or an optionally substituted phenyl group; and pharmaceutically acceptable salts thereof,
excluding compounds in which either at the same time R1 denotes C(CH3)3, R2 denotes hydrogen, R3 denotes unsubstituted phenyl, X denotes S and Y denotes N or CR6, where R6=hydrogen or CH2xe2x80x94CO2-ethyl, or at the same time R1 denotes C(CH3)3, R2 denotes hydrogen, R3 denotes unsubstituted phenyl, Y denotes NH and X denotes N or CR5, where R5xe2x95x90CO2ethyl.
Optionally substituted phenyl, optionally substituted 1-naphthyl, optionally substituted pyrrole, optionally substituted furfuryl, optionally substituted thiophene, optionally substituted isocyanate and optionally substituted alkyl, according to the instant invention, may be optionally substituted by one or more substituents selected from the group consisting of a halogen atom, cyano group, nitro group, carboxyl group, hydroxyl group, C1-C4 alkylamido group, C1-C4 alkylamino group, pyrrolidino group, branched or unbranched C1-C6 alkyl group, C1-C4 alkyl group substituted with one or more halogen atoms, C1-C4 alkoxy group, C1-C4 alkoxy group substituted with one or more halogen atoms, and halogen substituted phenoxy group.
Where R3 is a substituted phenyl group, it is preferably 4-acetamidophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-bromo-2-fluorophenyl, 5-bromo-2-fluorophenyl, 3-bromo-4-fluorophenyl, 4-tert-butylphenyl, 2-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-cyanophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-hexylphenyl, 3-hydroxyphenyl, 2-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-nitrophenyl, 3-phenoxyphenyl, 4-(1-pyrrolidino)phenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 3,4,5-trimethoxyphenyl, 3-(4-chlorophenoxy)phenyl or 4-acetoxy-3-methoxyphenyl.
Where R3 is a substituted 1-naphthyl group, it is preferably 4-dimethylaminonaphthyl, 2-ethoxynaphthyl or 4-methoxynaphthyl.
Where R3 is a substituted pyrrole group, it is preferably 2-(1-(phenylsulfonyl)-pyrrole), 2-(N-methylpyrrole), 2-(N-(3,5-dichlorophenyl)-pyrrole or 2-(1-(4-chlorophenyl)pyrrole).
Where R3 is a substituted furfuryl group, it is preferably 2-(5-acetoxymethylfurfuryl), 2-(5-methylfurfuryl), 2-(5-nitrofurfuryl), 2-[5-(3-nitrophenyl)furfuryl], 2-[5-(2-nitrophenyl)furfuryl], 2-(5-bromofurfuryl), 2-[5-(4-chlorophenyl)furfuryl], 2-(4,5-dimethylfurfuryl), 2-[5-(2-chlorophenyl)furfuryl], 2-(5-ethylfurfuryl) or 2-[5-(1,3-dioxalane)furfuryl].
Where R3 is a substituted thiophene group, it is preferably 2-(5-chlorothiophenyl), 2-(5-methylthiophenyl), 2-(5-ethylthiophenyl), 2-(3-methylthiophenyl), 2-(4-bromothiophenyl), 2-(5-nitrothiophenyl), 5-(2-carboxythiophenyl), 2-[4-(phenylethyl)thiophenyl], 2-[5-(methylthio)thiophenyl], 2-(3-bromothiophenyl), 2-(3-phenoxythiophenyl) or 2-(5-bromothiophenyl).
Where Rb is a substituted phenyl group, it is preferably 3,5-bis(trifluoromethyl)phenyl, 2-bromophenyl, 2-fluorophenyl, pentafluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 2,4-dichlorophenyl, 2-acetylphenyl, 2-methoxyphenyl, 2,6-dimethoxyphenyl, 2-(trifluoromethyl)phenyl, 2-methylphenyl, 3-bromophenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3,5-dimethoxyphenyl, 3-(trifluoromethyl)phenyl, 3-methoxyphenyl, 4-bromophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-(trifluoromethyl)phenyl, 4-tert-butylphenyl, 4-methylphenyl, 2-iodophenyl, 4-iodophenyl, 4-cyanophenyl, 2-nitrophenyl, 3-nitrophenyl, 3,5-dinitrophenyl, 4-nitrophenyl, 3,5-dichlorophenyl, 2,5-difluorophenyl, 2,4-dimethoxyphenyl, 3-nitro-4-methylphenyl, 2,5-dichlorophenyl, 2,3-difluorophenyl, 4-(trifluoromethoxy)phenyl, 2-(trifluoromethoxy)phenyl or 3-(trifluoromethoxy)phenyl.
Where Rc is a substituted phenyl group, it is preferably 2-fluorophenyl, 2-chlorophenyl, 2-methylphenyl, 2-(trifluoromethyl)phenyl, 2-bromophenyl, 3-methoxyphenyl, 3-nitrophenyl, 3-chlorophenyl, 3-fluorophenyl, 3-phenoxyphenyl, 3-(trifluoromethoxy)phenyl, 3-bromophenyl, 3-chlorophenyl, 3-methylphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-vinylphenyl, 4-(trifluoromethoxy)phenyl, 3,5-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-di(trifluoromethyl)phenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl 2,3-dichlorophenyl, 2,3-dimethylphenyl, 2,3-difluorophenyl, 3-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, 2,4-di(trifluoromethyl)phenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,4-dimethylphenyl, 2,5-dichlorophenyl, 2,5-dimethylphenyl, 2,5-difluorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-dimethylphenyl, 2,3,4-trifluorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trimethylphenyl or pentafluorophenyl.
Where Rd is a substituted phenyl group, it is preferably 3-chlorophenyl, 4-chlorophenyl, 4-carboxyphenyl, 4-acetylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-nitrophenyl or 4-hydroxyphenyl.
Bicyclic imidazo-5-yl-amines which are particularly preferred according to the invention are tert-butyl-(5-furan-2-yl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
tert-butyl-(6-furan-2-yl-imidazo[2,1-b]thiazol-5-yl)-amine,
(5-tert-butylamino-6-furan-2-yl-imidazo[2,1-b]thiazol-3-yl)-acetic acid,
tert-butyl-(5-pyridin-2-yl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
tert-butyl-(6-pyridin-2-yl-imidazo[2,1-b]thiazol-5-yl)-amine,
tert-butyl-(5-pyridin-3-yl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
tert-butyl-(5-pyridin-4-yl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
tert-butyl-(6-cyclohexyl-imidazo[2,1-b]thiazol-5-yl)-amine,
tert-butyl-(5-methyl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
tert-butyl-(6-methyl-imidazo[2,1-b]thiazol-5-yl)-amine,
cyclohexyl-(5-pyridin-2-yl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
cyclohexyl-(6-pyridin-2-yl-imidazo[2,1-b]thiazol-5-yl)-amine,
(5-cyclohexylamino-6-pyridin-2-yl-imidazo[2,1-b]thiazol-3-yl)-acetic acid,
cyclohexyl-(6-pyridin-4-yl-imidazo[2,1-b]thiazol-5-yl)-amine,
cyclohexyl-(6-cyclohexyl-imidazo[2,1-b]thiazol-5-yl)-amine,
(6-cyclohexyl-5-cyclohexylamino-imidazo[2,1-b]thiazol-3-yl)-acetic acid,
(5-cyclohexylamino-6-methyl-imidazo[2,1-b]thiazol-3-yl)-acetic acid,
(2,6-dimethyl-phenyl)-(5-furan-2-yl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
(2,6-dimethyl-phenyl)-(6-pyridin-2-yl-imidazo[2,1-b]thiazol-5-yl)-amine,
(2,6-dimethyl-phenyl)-(6-pyridin-3-yl-imidazo[2,1-b]thiazol-5-yl)-amine,
(2,6-dimethyl-phenyl)-(6-pyridin-4-yl-imidazo[2,1-b]thiazol-5-yl)-amine,
methyl (6-cyclohexyl-imidazo[2,1-b]thiazol-5-ylamino)-acetate,
methyl (6-methyl-imidazo[2,1-b]thiazol-5-ylamino)-acetate,
tert-butyl-(2-phenyl-5H-imidazo[1,2-b]pyrazol-3-yl)-amine,
3-(5-tert-butylamino-imidazo[2,1-b]thiazol-6-yl)-phenol,
tert-butyl-[6-(3,4-dimethoxy-phenyl)-imidazo[2,1-b]thiazol-5-yl]-amine,
tert-butyl-[5-(2,3-dichloro-phenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-amine,
tert-butyl-[6-(2,3-dichloro-phenyl)-imidazo[2,1-b]thiazol-5-yl]-amine,
tert-butyl-[5-(2,4-dichloro-phenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-amine,
tert-butyl-[6-(2,4-dichloro-phenyl)-imidazo[2,1-b]thiazol-5-yl]-amine,
tert-butyl-[5-(2-methoxy-phenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-amine,
tert-butyl-[6-(2-methoxy-phenyl)-imidazo[2,1-b]thiazol-5-yl]-amine,
[5-tert-butylamino-6-(2-methoxy-phenyl)-imidazo[2,1-b]thiazol-3-yl]-acetic acid,
tert-butyl-(5-o-tolyl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
tert-butyl-(6-o-tolyl-imidazo[2,1-b]thiazol-5-yl)-amine,
tert-butyl-[5-(2,3-dimethoxy-phenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-amine,
tert-butyl-[6-(2,3-dimethoxy-phenyl)-imidazo[2,1-b]thiazol-5-yl]-amine,
tert-butyl-(6-p-tolyl-imidazo[2,1-b]thiazol-5-yl)-amine,
(5-tert-butylamino-6-methyl-imidazo[2,1-b]thiazol-3-yl)-acetic acid,
N-tert-butyl-N-(6-phenyl-imidazo[2,1-b]thiazol-5-yl)-acetamide,
N-tert-butyl-N-(6-o-tolyl-imidazo[2,1-b]thiazol-5-yl)-acetamide,
butyl-[6-(4-tert-butyl-phenyl)-2-methyl-imidazo[2,1-b]thiazol-5-yl]amine,
tert-butyl-[5-(2-fluorophenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-amine,
tert-butyl-[6-(2-fluorophenyl)-imidazo[2,1-b]thiazol-5-yl]-amine,
tert-butyl-(5-naphthalen-1-yl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
cyclohexyl-(5-naphthalen-1-yl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
[5-(2-bromophenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-(1,1,3,3-tetramethyl-butyl)-amine,
N-[4-(6-cyclohexylamino-imidazo[1,2-b][1,2,4]triazol-5-yl)-phenyl)-acetamide,
tert-butyl-[5-(2,5-dimethyl-phenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-amine,
cyclohexyl-[6-(2,4-dimethyl-phenyl)-imidazo[2,1-b]thiazol-5-yl]-amine,
cyclohexyl-[6-(2,5-dimethylphenyl)-imidazo[2,1-b]thiazol-5-yl]-amine,
N-tert-butyl-N-(6-p-tolyl-imidazo[2,1-b]thiazol-5-yl)-acetamide,
[5-(2,4-dimethyl-phenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-(1,1,3,3-tetramethyl-butyl)-amine,
[5-(2,5-dimethyl-phenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-(1,1,3,3-tetramethyl-butyl)-amine,
N-butyl-N-[5-(2-chloro-6-fluorophenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-acetamide or
N-butyl-N-[6-(4-tert-butyl-phenyl)-2-methyl-imidazo[2,1-b]thiazol-5-yl]-acetamide.
If the bicyclic imidazo-5-yl-amines according to the invention contain optically active carbon atoms, the present invention also provides the enantiomers of these compounds and mixtures thereof. The present invention also provides pharmaceutically acceptable salts thereof.
The invention furthermore provides medicaments or pharmaceutical compositions comprising as the active compound at least one bicyclic imidazo-5-yl-amine of the general formula I, in which R1 to R6, X and Y have the abovementioned meaning, in the form of the base or of pharmaceutically acceptable salts, preferably of hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid, or in particular of hydrochloric acid.
The medicaments according to the invention particularly preferably comprise as the active compound at least one bicyclic imidazo-5-yl-amine chosen from the group consisting of
tert-butyl-(5-furan-2-yl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
tert-butyl-(6-furan-2-yl-imidazo[2,1-b]thiazol-5-yl)-amine,
(5-tert-butylamino-6-furan-2-yl-imidazo[2,1-b]thiazol-3-yl)-acetic acid,
tert-butyl-(5-pyridin-2-yl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
tert-butyl-(6-pyridin-2-yl-imidazo[2,1-b]thiazol-5-yl)-amine,
tert-butyl-(5-pyridin-3-yl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
tert-butyl-(5-pyridin-4-yl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
tert-butyl-(6-cyclohexyl-imidazo[2,1-b]thiazol-5-yl)-amine,
tert-butyl-(5-methyl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
tert-butyl-(6-methyl-imidazo[2,1-b]thiazol-5-yl)-amine,
cyclohexyl-(5-pyridin-2-yl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
cyclohexyl-(6-pyridin-2-yl-imidazo[2,1-b]thiazol-5-yl)-amine,
(5-cyclohexylamino-6-pyridin-2-yl-imidazo[2,1-b]thiazol-3-yl)-acetic acid,
cyclohexyl-(6-pyridin-4-yl-imidazo[2,1-b]thiazol-5-yl)-amine,
cyclohexyl-(6-cyclohexyl-imidazo[2,1-b]thiazol-5-yl)-amine,
(6-cyclohexyl-5-cyclohexylamino-imidazo[2,1-b]thiazol-3-yl)-acetic acid,
(5-cyclohexylamino-6-methyl-imidazo[2,1-b]thiazol-3-yl)-acetic acid,
(2,6-dimethyl-phenyl)-(5-furan-2-yl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
(2,6-dimethyl-phenyl)-(6-pyridin-2-yl-imidazo[2,1-b]thiazol-5-yl)-amine,
(2,6-dimethyl-phenyl)-(6-pyridin-3-yl-imidazo[2,1-b]thiazol-5-yl)-amine,
(2,6-dimethyl-phenyl)-(6-pyridin-4-yl-imidazo[2,1-b]thiazol-5-yl)-amine,
methyl (6-cyclohexyl-imidazo[2,1-b]thiazol-5-ylamino)-acetate,
methyl (6-methyl-imidazo[2,1-b]thiazol-5-ylamino)-acetate,
tert-butyl-(2-phenyl-5H-imidazo[1,2-b]pyrazol-3-yl)-amine,
3-(5-tert-butylamino-imidazo[2,1-b]thiazol-6-yl)-phenol,
tert-butyl-[6-(3,4-dimethoxy-phenyl)-imidazo[2,1-b]thiazol-5-yl]-amine,
tert-butyl-[5-(2,3-dichloro-phenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-amine,
tert-butyl-[6-(2,3-dichloro-phenyl)-imidazo[2,1-b]thiazol-5-yl]-amine,
tert-butyl-[5-(2,4-dichloro-phenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-amine,
tert-butyl-[6-(2,4-dichloro-phenyl)-imidazo[2,1-b]thiazol-5-yl]-amine,
tert-butyl-[5-(2-methoxy-phenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-amine,
tert-butyl-[6-(2-methoxy-phenyl)-imidazo[2,1-b]thiazol-5-yl]-amine,
[5-tert-butylamino-6-(2-methoxy-phenyl)-imidazo[2,1-b]thiazol-3-yl]-acetic acid,
tert-butyl-(5-o-tolyl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
tert-butyl-(6-o-tolyl-imidazo[2,1-b]thiazol-5-yl)-amine,
tert-butyl-[5-(2,3-dimethoxy-phenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-amine,
tert-butyl-[6-(2,3-dimethoxy-phenyl)-imidazo[2,1-b]thiazol-5-yl]-amine,
tert-butyl-(6-p-tolyl-imidazo[2,1-b]thiazol-5-yl)-amine,
(5-tert-butylamino-6-methyl-imidazo[2,1-b]thiazol-3-yl)-acetic acid,
N-tert-butyl-N-(6-phenyl-imidazo[2,1-b]thiazol-5-yl)-acetamide,
N-tert-butyl-N-(6-o-tolyl-imidazo[2,1-b]thiazol-5-yl)-acetamide,
butyl-[6-(4-tert-butyl-phenyl)-2-methyl-imidazo[2,1-b]thiazol-5-yl]amine,
tert-butyl-[5-(2-fluorophenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-amine,
tert-butyl-[6-(2-fluorophenyl)-imidazo[2,1-b]thiazol-5-yl]-amine,
tert-butyl-(5-naphthalen-1-yl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
cyclohexyl-(5-naphthalen-1-yl-imidazo[1,2-b][1,2,4]triazol-6-yl)-amine,
[5-(2-bromophenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-(1,1,3,3-tetramethyl-butyl)-amine,
N-[4-(6-cyclohexylamino-imidazo[1,2-b][1,2,4]triazol-5-yl)-phenyl)-acetamide,
tert-butyl-[5-(2,5-dimethyl-phenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-amine,
cyclohexyl-[6-(2,4-dimethyl-phenyl)-imidazo[2,1-b]thiazol-5-yl]-amine,
cyclohexyl-[6-(2,5-dimethylphenyl)-imidazo[2,1-b]thiazol-5-yl]-amine,
N-tert-butyl-N-(6-p-tolyl-imidazo[2,1-b]thiazol-5-yl)-acetamide,
[5-(2,4-dimethyl-phenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-(1,1,3,3-tetramethyl-butyl)-amine,
[5-(2,5-dimethyl-phenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-(1,1,3,3-tetramethyl-butyl)-amine,
N-butyl-N-[5-(2-chloro-6-fluorophenyl)-imidazo[1,2-b][1,2,4]triazol-6-yl]-acetamide and
N-butyl-N-[6-(4-tert-butyl-phenyl)-2-methyl-imidazo[2,1-b]thiazol-5-yl]-acetamide, in the form of the base or of pharmaceutically acceptable salts.
The compounds according to the invention are ligands of the pain-relevant xcex12-subtype of the human xcex1-adrenergic receptor. The use of the bicyclic imidazo-5-yl-amines according to the invention together with one or more auxiliary substances for the preparation of a medicament for combating pain, or method for treating pain comprising administering a pharmaceutically acceptable effective amount of the bicyclic imidazo-5-yl-amines to a patient in need thereof, is therefore particularly preferred.
For the preparation of appropriate medicaments, in addition to at least one active compound according to the invention, carrier materials, fillers, solvents, diluents, dyestuffs, binders and/or other pharmaceutically acceptable excipients are employed. The choice of auxiliary substances and the amounts thereof to be employed depend on whether the medicament is to be administered orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or locally. Formulations in the form of tablets, coated tablets, capsules, granules, drops, juices and syrups are suitable for oral administration, and solutions, suspensions, easily reconstitutable dry formulations and sprays are suitable for parenteral, topical and inhalatory administration. Active compounds according to the invention in a depot, in dissolved form or in a patch, optionally with the addition of agents which promote penetration through the skin, are suitable formulations for percutaneous administration. Formulation forms which can be used orally or percutaneously can release the active compounds according to the invention in a retarded manner.
The amount of active compound to be administered to the patient varies according to the body weight of the patient, and to the mode of administration, the indication and the severity of the disease.
The compounds according to the invention are synthesized by a procedure in which an amidine with the general formula II, in particular 3-aminopyrazole, 3-amino-1,2,4-triazole, 2-amino, 1,3,4-thiadiazole or a 2-aminothiazole derivative, which are commercially available from companies such as Acros, Avocado, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma or TCI-Jp, are reacted with the most diverse aldehydes III and isonitriles IV in the presence of 20% perchloric acid in accordance with a three-component reaction to form a compound of the formula Ia (see below). R1 to R3, X and Y here have the meaning given above for compounds of the formula I. 
The reactions are preferably carried out in methylene chloride (MC) at a temperature of 0xc2x0 C. to 40xc2x0 C., in particular at 10xc2x0 C. to 20xc2x0 C.
To prepare the compounds according to the invention in which R2 does not denote hydrogen, the compounds Ia formed in the reaction described above, which have preferably first been dissolved in methylene chloride or THF (5-hydroxymethylene tetrahydrofolate, or tetrahydrofuran), are reacted, depending on the desired end product, with a compound R2Hal, wherein Hal represents bromine, iodine or, in particular, chlorine, for example an optionally substituted alkyl, aryl or acid chloride, or an optionally substituted isocyanate ReNCO in the presence of a morpholine resin (e.g. polystyrene-morpholine from Argonaut) in methylene chloride in the course of 2 to 24 hours at temperatures between 10xc2x0 C. and 40xc2x0 C. in accordance with the following equation: 
The excess reagents are then removed from the reaction mixture by filtration over a layer with polymer-bonded tris(2-aminoethyl)amine (manufacturer: Novabiochem) or 3-(3-mercaptophenyl)propanamidomethylpolystyrene and the filtrate is preferably concentrated in a vacuum centrifuge. The entire process can also easily be carried out in an automated synthesis unit.
The compounds of the formula I can be converted into their pharmaceutically acceptable salts in a manner well-known to those ordinarily skilled in the art with physiologically tolerated acids, preferably hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid, and in particular hydrochloric acid. The salt formation is preferably carried out in a solvent, in particular diethyl ether, diisopropyl ether, acetic acid alkyl esters, acetone or 2-butanone, or a mixture of these solvents. Alternatively, trimethylsilane in aqueous solution is also suitable for preparation of the hydrochlorides.